Systemic lupus erythematosus (SLE) is characterized by IgG autoantibodies to certain intracellular components, including chromatin and ribonucleoproteins. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Certain of these specificities are pathogenic, including those against chromatin that induce immune-complex glomerulonephritis. Autoantibodies in lupus arise as a consequence of autoantigen-specific alpha/beta CD4+ T cell help, including T cells specific for peptides of chromatin-associated proteins. Such autoreactive T cells bypass normal tolerance mechanisms in the periphery; however, the mechanism of activation of T cells responsive to self peptides in lupus is unknown, as are the tissue source(s) of such peptides and the events leading to autoreactive CD4+ T cell-B cell collaboration with resultant pathogenic autoantibody production. In this proposal, an in vivo approach will be used to dissect the mechanisms that lead to peripheral T cell tolerance abrogation and T cell help for autoantibody production in lupus. It is hypothesized that these events arise in two stages: first, that lupus T cells have intrinsic (genetic) defects that render them susceptible to activation after contact with the ubiquitous self peptide-class II MI-IC complexes that are sufficient for CD4+ T cell survival in normal animals; second, that such activation, initiating tolerance loss with polyclonal expansion of autoreactive T cells, leads to oligoclonal T-B cell collaboration in the setting of specific autoantigen presentation by autoreactive B cells. The hypothesis will be addressed in two aims. First, it will be determined if normally displayed (ubiquitous) MHC-self peptide complexes can activate autoreactive T cells from Fas-intact mice MRL/+Fas-lpr mice, in comparison to non-autoimmune control T cells. Second, it will be determined if T cells from MRL/+Fas-lpr mice can provide B cell help in the setting of autoantigen presentation by autoreactive B cells, an event that leads to antigen-specific expansion of cells from both lineages. These objectives fit well within the overall context of this IRPO proposal centered around developing a better understanding of T cell-B cell interactions during the development and maintenance of systemic autoimmunity.